Our goal is to understand variability in the rates and patterns of mutation among regions of the human genome and the causes of this variation. Specifically, we shall address the following issues: 1. How different are the mutation rates among homologous sequences on different types of chromosome (autosomes, X chromosome, and Y chromosome)? The aim is to estimate the magnitude of difference between male and female mutation rates. 2. How variable are the mutation rates among regions of a chromosome or chromosomes of the same type? 3. Does the pattern of mutation different among genomic regions? Issues 2 and 3 are the essence of the regional mutation pressure hypothesis, which postulates that the rate and pattern of mutation varies among regions of the mammalian genome. We shall test this hypothesis and study the origin and evolution of GC-rich isochores. 4. Is the variation in the level of single nucleotide polymorphism (SNO) among human genomic regions due in a large extent to variations in mutation rate. To study these issues, we propose to pursue the following work. 1. To search for pairs of non-coding regions that are homologous (very similar) between X and Y chromosomes, or between Y and an autosome, or between X and an autosome, and choose several (5 to 7) pairs of regions that are suitable for estimating sex differences in mutation rate. Each pair of regions will be sequenced in several higher primates (e.g.. chimpanzee, gorilla, orangutan, siamang, gibbon, and possibly Old World monkeys. 2. Select approximately 15 unique Y-linked DNA segments each of 2-5 kb in length, These segments should be non-coding, should have no homologue on any autosome or X chromosome, and should have a wide coverage of GC contents. Sequence each segment in several higher primates. 3. Similarly, select approximately 50 unique autosomal DNA segments each of approximately 5 kb in length. We will try to select segments that have SNP data and have suitable GC contents and recombination rates. Sequence each of them in chimpanzee, gorilla, orangutan, siamang, baboon and colobus. 4. To conduct statistical analyses of the new and existing data to address the above issues.